Differentiation of human marrow stromal precursor cells: bone morphogenetic protein-2 increases OSF2/CBFA1, enhances osteoblast commitment, and inhibits late adipocyte maturation.

Because regulation of the differentiation to osteoblasts and adipocytes from a common progenitor in bone marrow stroma is poorly understood, we assessed effects of bone morphogenetic protein-2 (BMP-2) on a conditionally immortalized human marrow stromal cell line, hMS(2-6), which is capable of differentiation to either lineage. BMP-2 did not affect hMS(2-6) cell proliferation but enhanced osteoblast differentiation as assessed by a 1.8-fold increase in expression of OSF2/CBFA1 (a gene involved in commitment to the osteoblast pathway), by increased mRNA expression and protein secretion for alkaline phosphatase (ALP), type I procollagen and osteocalcin (OC) (except for OC protein), and by increased mineralized nodule formation. Transient transfection with Osf2/Cbfa1 antisense oligonucleotide substantially reduced BMP-2-stimulated expression of ALP mRNA and protein. The effects of BMP-2 on adipocyte differentiation varied: expression of peroxisome proliferator-activated receptor gamma2 (a gene involved in commitment to the adipocyte pathway) was unchanged, mRNA expression of the early differentiation marker, lipoprotein lipase, was increased, and mRNA and protein levels of the late differentiation marker, leptin, and the formation of cytoplasmic lipid droplets were decreased. Thus, by enhancing osteoblast commitment and by inhibiting late adipocyte maturation, BMP-2 acts to shunt uncommitted marrow stromal precursor cells from the adipocyte to the osteoblast differentiation pathway.     

Narrative review of artificial intelligence in diabetic macular edema: Diagnosis and predicting treatment response using optical coherence tomography

Diabetic macular edema (DME), being a frequent manifestation of DR, disrupts the retinal symmetry. This event is particularly triggered by vascular endothelial growth factors (VEGF). Intravitreal injections of anti-VEGFs have been the most practiced treatment but an expensive option. A major challenge associated with this treatment is determining an optimal treatment regimen and differentiating patients who do not respond to anti-VEGF. As it has a significant burden for both the patient and the health care providers if the patient is not responding, any clinically acceptable method to predict the treatment outcomes holds huge value in the efficient management of DME. In such situations, artificial intelligence (AI) or machine learning (ML)-based algorithms come useful as they can analyze past clinical details of the patients and help clinicians to predict the patient''s response to an anti-VEGF agent. The work presented here attempts to review the literature that is available from the peer research community to discuss solutions provided by AI/ML methodologies to tackle challenges in DME management. Lastly, a possibility for using two different types of data has been proposed, which is believed to be the key differentiators as compared to the similar and recent contributions from the peer research community.     

Use of femur length/abdominal circumference ratio in detecting the macrosomic fetus

The femur length/abdominal circumference ratio, expressed as FL/AC X 100, was determined in 156 fetuses and evaluated as a predictor of fetal macrosomia within one week prior to delivery. The normal range (mean +/- 2 SD) in the 105 normal-weight fetuses was 22.0 +/- 2, while the normal range in the 51 macrosomic fetuses was 20.5 +/- 2; these differences were highly significant (P = less than .0001). The predictive power of a positive ratio was 68%, with a sensitivity of 63%. This ratio was particularly useful in the subset (n = 9) of macrosomic fetuses whose mothers were diabetic, correctly identifying 89% of this group. Because it is age independent, this ratio should prove most helpful in identifying fetuses at risk for macrosomia in patients whose dates are not known, since it may become abnormal before the fetal weight falls above the 90th percentile at term (3,900 g). In patients whose dates are known, early fetal macrosomia is best predicted by evaluating the abdominal circumference against normal standards for age.     

Hutchinson-Gilford progeria syndrome: oral and craniofacial phenotypes

Objective:  Hutchinson-Gilford progeria syndrome (HGPS) is a rare early-onset accelerated senescence syndrome. In HGPS, a recently identified de novo dominant mutation of the lamin A gene ( LMNA ) produces abnormal lamin A, resulting in compromised nuclear membrane integrity. Clinical features include sclerotic skin, cardiovascular and bone abnormalities, and marked growth retardation. Craniofacial features include 'bird-like' facies, alopecia, craniofacial disproportion, and dental crowding. Our prospective study describes dental, oral soft tissue, and craniofacial bone features in HGPS.
Methods:  Fifteen patients with confirmed p.G608G LMNA mutation (1–17 years, seven males, eight females) received comprehensive oral evaluations. Anomalies of oral soft tissue, gnathic bones, and dentition were identified.
Results:  Radiographic findings included hypodontia ( n  = 7), dysmorphic teeth ( n  = 5), steep mandibular angles ( n  = 11), and thin basal bone ( n  = 11). Soft tissue findings included ogival palatal arch ( n  = 8), median sagittal palatal fissure ( n  = 7), and ankyloglossia ( n  = 7). Calculated dental ages (9 months to 11 years 2 months) were significantly lower than chronological ages (1 year 6 months to 17 years 8 months) ( P  = 0.002). Eleven children manifested a shorter mandibular body, anterior/posterior cranial base and ramus, but a larger gonial angle, compared to age/gender/race norms.
Conclusion:  Novel oral-craniofacial phenotypes and quantification of previously reported features are presented. Our findings expand the HGPS phenotype and provide additional insight into the complex pathogenesis of HGPS.     

2-methoxyestradiol induces interferon gene expression and apoptosis in osteosarcoma cells

2-Methoxyestradiol (2-ME), a naturally occurring mammalian metabolite of 17beta-estradiol, has been implicated as a physiological inhibitor of tumor cell proliferation. In this study, the effects of 2-ME on cultured osteosarcomatous cells were investigated. Dose-dependent growth inhibition was observed in MG63 and TE85 human osteosarcoma cells exposed to 2-ME. The cell killing by 2-ME was ligand-specific; the immediate precursor (2-hydroxyestradiol), the parent compound (17beta-estradiol), and the equivalent metabolite of estrone (2-methoxyestrone) exhibited less potency and efficacy. Furthermore, 2-ME was similarly effective at killing immortalized human fetal osteoblastic cells (hFOB) with and without estrogen receptor-alpha and -beta and rat osteosarcoma cells (ROS17/2.8). The cytotoxicity of 2-ME was selective to transformed and immortalized osteoblastic cells; 2-ME (2 microm) had no effect on the proliferation of primary cultures of human osteoblasts. Co-treatment with the potent estrogen receptor ligand, ICI-182,780, did not reduce 2-ME-induced osteosarcoma cell death, implying that this action is not mediated by conventional estrogen receptors. The expression levels of bone matrix protein genes, type 1 collagen and osteonectin, were transiently reduced after 2-ME treatment, suggesting that the surviving cells are capable of producing bone matrix. The 2-ME-mediated killing of osteosarcoma cells was due to the induction of apoptosis; treatment induced expression of interferon genes within 12 h and histological evidence of apoptosis within 48 h of 2-ME treatment. Thus, our results demonstrate that 2-ME is highly cytotoxic to osteosarcoma cells but not normal osteoblasts. These findings suggest that further study of 2-ME as a potential intervention for treatment of osteosarcoma is warranted.     

How common is polycystic ovary syndrome in recurrent miscarriage?

The association between polycystic ovary syndrome (PCOS) and recurrent miscarriage (RM) has been long established, but the relative importance of this condition as a cause of RM is far from clear. Previous studies on the prevalence of PCOS in RM have been hampered by a lack of objective and universally accepted criteria for the diagnosis of PCOS, resulting in considerable controversy. However, the Rotterdam criteria have since been accepted as the gold standard for diagnosis of PCOS, and therefore these criteria have been used to produce a much clearer and more objective assessment of the prevalence of PCOS in RM. Three hundred women with recurrent miscarriage were studied. A diagnosis of PCOS was established via measurement of cycle length and day 21 serum progesterone, determination of the free androgen index and pelvic ultrasonography. All ultrasound reports prior to publication of the Rotterdam criteria were reviewed, ensuring consistency in the diagnosis of a polycystic ovary. Ultrasound scans of 27 patients confirmed polycystic ovaries with a further 10 scans suggestive of polycystic ovaries, but with insufficient information for the Rotterdam criteria to be applied. Hence, 27–37 (9.0–12%) patients presented with ultrasonographic polycystic ovaries. Using the Rotterdam criteria, 25–30 (8.3–10%) patients had PCOS. It is concluded that the prevalence of PCOS in RM is considerably lower than has previously been accepted.     

The dose-response effects of ethanol on the human fetal osteoblastic cell line.

Alcohol is a risk factor for the development of osteoporosis, especially in men. Chronic alcohol abuse decreases bone mass, which contributes to the increased incidence of fractures. To better understand the mechanism of action of ethanol on bone metabolism, we have studied the dose-response effects of ethanol on conditionally immortalized human fetal osteoblasts (hFOB) in culture. Ethanol treatment had no significant effects on osteoblast number after 1 day or 7 days. Ethanol treatment did not reduce type I collagen protein levels at either time point at any dose but slightly reduced alkaline phosphatase activity after 7 days. The messenger RNA (mRNA) levels for alkaline phosphatase, type I collagen, and osteonectin were unaltered by 24 h of ethanol treatment but a high dose (200 mM) reduced mRNA levels for the two bone matrix proteins after 7 days. Ethanol treatment led to dose-dependent increases in transforming growth factor beta1 (TGF-beta1) mRNA levels and decreases in TGF-beta2 mRNA levels. The concentration of ethanol in the medium decreased with time because of evaporation but there was little degradation caused by metabolism. These results, which show that cultured osteoblasts are less sensitive than osteoblasts in vivo, suggest that the pronounced inhibitory effects of ethanol on bone formation are not caused by direct cell toxicity.     

Surgery for recurrent goitre: its complications and their risk factors.

OBJECTIVE: To find out the morbidity of reoperation for benign recurrent thyroid disease, and the risk factors associated with it. DESIGN: Retrospective study. SETTING: Specialist endocrine unit, Germany. SUBJECTS: 1031 patients operated on for recurrent goitre between 1 January 1983 and 31 December 1996. MAIN OUTCOME MEASURES: Incidence of recurrent laryngeal nerve palsy and hypocalcaemia. RESULTS: 82/1031 patients were excluded from assessment for recurrent laryngeal nerve function leaving 949 for analysis. There were no cases of bilateral permanent palsy, but 1 patient developed temporary bilateral palsy. 33 patients (3%) developed permanent unilateral palsy and 46 (5%) temporary palsy. 1307 nerves were at risk, and the rate of permanent palsy was therefore 2% of nerves at risk. This was 5 times the rate after the initial operation. Hyperthyroidism and not exposing the nerve during operation were predisposing factors. 118 patients were excluded from assessment of hypocalcaemia leaving 913 for analysis. 23 patients developed temporary hypocalcaemia (2%), but only 5 (0.5%) developed permanent hypocalcaemia. Because so few patients developed hypocalcaemia we were unable to designate risk factors. CONCLUSION: Because of the high risk of complications operations for recurrent goitre should be done only if the patient cannot be treated in any other way. The risk of recurrence should be minimised by excision of all nodules during the initial operation.